Highly active antiretroviral therapy (HAART) has been a major advance in treatment of AIDS in humans. HAART provides long term suppression of HIV-1 loads to undetectable levels in many patients. Nevertheless, HIV-1 remains in a latent or persistent form in these patients and can reemerge when drug therapy is discontinued. Another major barrier to HAART or other therapeutic approaches is the emergence of drug resistant and multi-drug resistant variants of HIV-1. A major goal of this project is to establish HAART-like therapy in an animal model. The goal is not to provide a drug testing system but rather to further develop the animal model system to the point where it can be useful for studies of AIDS therapy that are difficult or impossible to do in humans infected by HIV-1. In particular, the applicants wish to study sites of low level virus replication and latency/persistence during HAART. In addition, they wish to evaluate new strategies to minimize resistance and to eradicate the pool of virus that evades HAART. For this they will use a chimera of simian immunodeficiency virus (SIV) containing the HIV-1 reverse transcriptase (RT-SHIV), which will enable in vitro and in vivo studies of combinations containing nucleoside analogs and non-nucleoside inhibitors of reverse transcriptase (NNRT1). They will also use this model for studies of drug combinations that include protease inhibitors. Long-term goals are utilize the model to probe sites of virus replication and/or persistence in prolonged HAART, and to evaluate other intervention approaches in attempts to eradicate virus from reservoirs.